Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder caused by motor neuron death (Rowland et al., N. Engl. J. Med., 2001, 334, 1688-1700) and characterized in part by the presence of abnormal aggregates of insoluble protein in selectively vulnerable populations of neurons and glia. ALS, an orphan disease, is estimated to afflict about 87,000 people worldwide, but its prevalence would be much higher were it not for the fact that ALS patients survive for only 3 to 5 years on average after diagnosis. Approximately 10% of ALS cases are familial, with the rest of the cases being sporadic (Rowland et al., N. Engl. J. Med., 2001, 334, 1688-1700). Approximately 20% of the cases of familial ALS are caused by inherited mutations in the protein Cu/Zn superoxide dismutase (SOD1) (Rosen et al., Nature, 1993, 362, 59-62). Rodent models in mutant SOD1 are often used as a disease model because of its phenotypic and pathologic resemblance to sporadic and familial human ALS (Dal Canto et al., Brain Res., 1995, 676, 25-40; Wong, et al., Neuron, 1995, 14, 1105-1116; Bruijin et al., Science, 1998, 281, 1851-1854; Bruijn et al., Neuron, 1997, 18, 327-338; Wang et al., Hum. Mol. Genet., 2003, 12, 2753-2764; Wang et al., Neurobiol. Dis., 2002, 10, 128-138; Jonsson et al., Brain, 2004, 127, 73-88).
The causes of sporadic ALS remain unknown, and the clinical courses are variable, suggesting that multiple factors are involved. Different hypotheses have been proposed, such as glutamate-mediated excitotoxicity, impaired mitochondrial function, oxidative stress, and aberrant protein aggregation (Dib et al., Drugs, 2003, 63, 289-310; Strong et al., Pharmacology & Therapeutics, 2003, 98, 379-414; Kunst et al., Am. J. Hum. Genet., 2004, 75, 933-947; Bruijn et al., Annu. Rev. Neurosci, 2004, 27, 723-749; Dibernardo et al., Biochimica et Biophysica Acta, 2006, 1762, 1139-1149). Riluzole, which decreases glutamate excitotoxicity, is the only FDA approved ALS drug (Jimonet et al., J. Med. Chem., 1999, 42, 2828-2843.). However, it can only extend median survival life for 2 to 3 months, suggesting mechanisms other than glutamate-mediated excitotoxicity should be considered during ALS drug development (Miller et al., ALS and Other Motor Neuron Disorders, 2003, 4, 191-206; Taylor et al., Neurology, 2006, 67, 20-27).
Imbalances in protein homeostasis, which can be caused by cell stress or expression of certain mutant proteins, can result in the appearance of alternative conformational states that are able to self-associate to form protein aggregates and inclusion bodies. In familial as well as sporadic forms of ALS and mutant SOD1 transgenic models, aberrant protein aggregation has been reported as a common feature (Bruijin et al., Science, 1998, 281, 1851-1854; Leigh et al., Cytoskeletalpathology in Motor Neuron Diseases, in: Rowland, L. P. (Editor), Amyotrophic Lateral Sclerosis and Other Motor Neuron Disease, Raven Press, New York, 1991, pp. 3-pp. 23; Mather et al., Neurosci. Lett., 1993, 160, 13-16; Pasinelli et al., Neuron, 2004, 43, 19-30; Watanabe, et al., Neruobiol. Dis., 2001, 8, 933-941). The ubiquity of this feature in various forms of ALS suggests that perhaps drugs that inhibit aberrant protein aggregation may provide new and improved treatment options. Thus, there is an urgent need to identify and develop drugs for the treatment of ALS.